Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5353_Библиотеки_им_академика_М_И_Перельмана.pdf
382 Chapter 15 Thyroid disorders and pharmacological methods of contraception
Cold, physical exercise
Hypothalamus
Fasting, sepsis
TRH
Somatostatin
Anterior
pituitary
TRH
Thyroid
T
Figure 15.2 Regulation of thyroid hormone secretion.
Release of the thyroid hormones, triiodothyronine (T3) and
tetraiodothyronine (thyroxine; T4) is regulated by thyroidstimulating hormone (TSH) from the anterior pituitary. This in turn
is controlled by thyrotrophin-releasing hormone (TRH) from the
hypothalamus. The release of both TSH and TRH is inhibited by
increased concentrations of circulating thyroid hormones. Release
of TRH is increased in response to exposure to cold temperatures
and physical exercise, and decreased by fasting and sepsis as
indicated. TSH output from the anterior pituitary is inhibited by
somatostatin: , increases release; ⊖, decreases release.
T
3
4
of brain damage worldwide, sometimes irreversible.
Supplementing common foodstus (e.g. salt) with iodide
has reduced the global incidence of hypothyroidism
enormously, although sometimes over-enthusiastic
corrective measures have created problems of their own
(see below). Hypothyroidism due to iodide deciency is
reversible if iodide intake is increased. However, the brain
damage that occurs in babies born with the condition can
be irreversible unless treated promptly (see below).
15.1.3 Mechanism of action and effects
of thyroid hormones
yroid hormones act through a class of nuclear receptors,
termed TR, of which there are two types, designated TR
and TR. ese receptors are similar in many respects to
the receptors for glucocorticoids described in Chapter 9,
Section 9.3.2, with eects on gene transcription. ey
dier, though, in that in the absence of ligand they are
already bound to a specic stretch of DNA, called the
thyroid hormone response element, found in the
promoter region of each target gene. When the receptor is
occupied by thyroid hormone, a conformational change
occurs, leading to alterations in the transcriptional activity
of the gene. Often this involves an increase in
transcription, leading to increased protein synthesis. It
should be noted, however, that some genes are repressed
by thyroid hormones. For example, synthesis of TSH, TRH,
and deiodinase enzymes are all decreased, contributing to
the negative feedback eects of increased circulating
levels of thyroid hormones (see Figure 15.2).
e secretion of both TRH and TSH by the hypothalamus
and the anterior pituitary, respectively, is subject to
feedback inhibition by increased levels of thyroid
hormones (particularly T3) in the blood. is tight
feedback control thereby maintains stable concentrations
of circulating thyroid hormones. e feedback is exerted
primarily at the level of the anterior pituitary, with thyroid
hormones directly inhibiting TSH output as well as
reducing the eectiveness of TRH. A number of
additional factors inuence the secretion of TRH and
TSH, as shown in Figure 15.2.
Role of dietary iodide
e iodide required for thyroid hormone production must
be supplied in the diet. Hypothyroidism due to iodide
deciency is extremely common worldwide, with up to
1.5 billion people at risk, and is the most prevalent cause
Receptors for thyroid hormones are expressed in virtually
all tissues, and mediate eects on metabolic processes,
and on growth and development (summarized in Table
15.1). eir activation signals an increase in basal
metabolic rate—the amount of energy used by the body
while at rest. e metabolic processes enhanced by
thyroid hormones include lipolysis, glycogenolysis, and
gluconeogenesis, increasing the availability of
expendable forms of energy. In keeping with their overall
eect, thyroid hormones also promote absorption of
glucose from the gastrointestinal tract. e resultant rise
in metabolic rate stimulates heat production, which is
supplemented by direct stimulation of thermogenesis in
brown adipose tissue by thyroid hormones.
Many of the eects of thyroid hormones are brought
about in tandem with other hormones. For instance,
thyroid hormones increase the expression of
adrenoceptors and potentiate the responsiveness of cells
15.2 Thyroid dysfunction 383
Table 15.1 Effects of thyroid hormones
Effects on metabolism
• Lipids Stimulate release of fatty acids from adipose tissue (fat mobilization)
Decrease levels of circulating triglycerides and low density lipoprotein (LDL)
Increased cholesterol utilization and excretion
• Carbohydrate Increase glucose absorption in the small intestine
Increase hepatic gluconeogenesis and glycogenolysis, and decreased glycogen synthesis
Effects on growth and
development
Other effects
• Cardiovascular Increase cardiac contractility and heart rate (both direct action and increasing
• Centralnervoussystem Low levels lead to loss of mental alertness in adults
• Reproductive Low levels associated with infertility in both males and females
Essential for growth (acting in concert with growth hormone) and regeneration of tissues
Crucial for normal development of central nervous system before and after birth; low
levels lead to impaired brain development in children, causing severe mental retardation
(cretinism)
responsiveness of target cells to adrenaline and noradrenaline)
Promotes vasodilatation
High levels lead to anxiety and nervousness
to adrenaline and noradrenaline. is sympathomimetic
action of thyroid hormones is clearly observed where
thyroid hormone secretion is elevated in hyperthyroidism
(see below). Sunita, the ctional patient in Workbook 12
who has a hyperactive thyroid, experiences symptoms
that match those of overactivity in the sympathetic
nervous system, including gastrointestinal problems,
palpitations, tachycardia, nervousness, and insomnia.
yroid hormones are essential for normal growth and
development. ey have direct actions, as well as
enhancing the synthesis and actions of growth hormone
and insulin-like growth factor-1. Overall they stimulate
bone growth, and synthesis of structural proteins. ese
hormones are also crucial to the development of the
central nervous system both in utero and after birth.
yroid-decient children show both stunted growth and
severe mental retardation (cretinism).
15.2 Thyroid dysfunction
Abnormalities in thyroid function are amongst the most
common endocrine disorders.
15.2.1 Hyperthyroidism
Hyperthyroidism results from excessive production and
release of thyroxine (T4) and triiodothyronine (T3) from
the thyroid glands, and can lead to thyrotoxicosis, the
clinically observed eects of prolonged exposure of tissues
Goitre
Excessive stimulation of the thyroid gland by TSH can
result in an enlarged thyroid gland—a goitre. It can be a
feature of both hyper- and hypothyroidism. Where
hypothyroidism arises from lack of dietary iodide, TSH
levels increase in an attempt to bolster the low levels of
circulating thyroid hormones. TSH stimulates an increase
in both the size (hypertrophy), and number (hyperplasia)
of follicular cells, and promotes vascularization of the
follicles through proliferation of the surrounding
capillaries. Overall there is an enlargement of the gland
(endemic goitre), which in the absence of iodide remains
unable to correct the decit in thyroid hormones.
Likewise, hyperthyroidism can (but does not always) lead
to a goitre, for example where TRH or TSH secretion is
excessive because of a hypothalamic or pituitary defect.
to elevated levels of thyroid hormones. ese eects
include an increase in basal metabolic rate and adrenergic
overactivity, resulting in a range of symptoms, including
weight loss, increased heart rate, anxiety, insomnia,
sweating, fatigue, and nervousness. e increased levels of
thyroid hormones lead to a decreased output of TSH by
the anterior pituitary, through feedback inhibition
(Figure 15.2). As described above, this is largely achieved by
384 Chapter 15 Thyroid disorders and pharmacological methods of contraception
Non-immunologically mediated hyperthyroidism
Hyperthyroidism can also be caused by tumour-like
growths within the thyroid glands that do not respond to
hypothalamic control. Examples of such conditions are
toxic multinodular goitre and toxic nodules (benign
thyroid adenomas). Inammation of the thyroid gland,
for example following viral infection, can also lead to
Figure 15.3 Exophthalmos in a patient with Graves’
disease.
From Roncevic R, Savkovic Z, Roncevic D. Results of diplopia
and strabismus in patients with severe thyroid ophthalmopathy
after orbital decompression. Indian J Ophthalmol 2014; 62(3):
268–273. © Indian Journal of Ophthalmology.
a decreased responsiveness of the anterior pituitary to
thyrotrophin-releasing hormone (TRH) secreted from the
hypothalamus. Hyperthyroidism is most commonly the
result of an autoimmune condition, although nonimmunologically mediated hyperthyroidism can also occur.
hyperthyroidism, although this is soon reversed through
the usual feedback pathways. Small lumps or nodules
may commonly appear on the thyroid, and usually
resolve without requiring intervention; incidence may be
as high as 5% of the adult population.
Toxic multinodular goitre (also called Plummer’s disease)
results from autonomously functioning nodules in the
thyroid gland which hypersecrete thyroid hormones. It is
the second most common cause of hyperthyroidism. is
condition does not lead to a goitre; the excessive production
of T3 and T4 suppresses TSH levels, and so growth of the
thyroid gland is not promoted. (e tumour itself may lead
to an enlargement of the thyroid, distinct from a goitre.)
Immunological hyperthyroidism
is type of hyperthyroidism is characterized by a diuse
enlargement of the thyroid glands. ese conditions are
roughly ve times more frequent in women than in men,
and often show familial traits. Graves’ disease is the most
common form. It aects one to two people per 1000 each
year; around 90% of suerers are young women, often
with a family history of the disease. It is an autoimmune
condition in which abnormal IgG immunoglobulin
(thyroid-stimulating immunoglobulin) is raised, which
binds and activates the TSH receptors on the follicular
cells in the thyroid gland. is leads to enhanced and
sustained receptor stimulation, resulting in increased
thyroid hormone production and growth of the thyroid
gland (a goitre can ensue). e stimulation is not subject
to the usual feedback inhibition exerted by increased
thyroid hormone levels, and therefore hormone secretion
and growth continue unchecked.
In addition to the symptoms mentioned above, Graves’
disease is associated with exophthalmos (protruding
eyeballs), which results from swelling caused by immunemediated inammatory responses in the ocular fat and
muscle (Figure 15.3). Where severe, exophthalmos can
lead to blindness through compression of the optic nerve.
is feature of Graves’ disease may be treated with
glucocorticosteroids to target the underlying
inammation (see Chapter 9, Section 9.3.2).
e anti-arrhythmia drug amiodarone is rich in iodine,
and can induce thyroid gland dysfunction (either
hyper- or hypothyroidism).
An acute, potentially life-threatening situation can arise
from severe hyperthyroidism. e release of excessive
levels of thyroid hormone leads to increases in heart rate,
blood pressure, and body temperature, which can reach
dangerous levels. e condition, known as a thyrotoxic crisis
or thyroid storm, can occur suddenly as a rare complication
of untreated or undermanaged hyperthyroidism.
Management of hyperthyroidism
Hyperthyroidism is managed by either decreasing the
synthesis or release of thyroid hormones, or blunting
their eects.
Radioactive iodide In hyperthyroidism, decreased
production of thyroid hormones can be achieved by
ablation of the thyroid gland, either through surgery or
administration of radioactive iodide. e iodide isotope
131
I, is given orally, and is taken up by the iodide pump on
the thyroid follicular cells, in the same way as nonradioactive iodide. It is incorporated into the
thyroglobulin molecules and emits - and -rays. e
-rays pass through the body without causing damage.
e -radiation, though, has low energy and is absorbed
by the thyroid tissue, causing destruction of the hormonesynthesizing cells. Treatment of hyperthyroidism by
15.2 Thyroid dysfunction 385
S
radioiodine is very eective; hypothyroidism will almost
inevitably follow, requiring lifelong thyroxine treatment.
Radioiodine has been used for the treatment of
hyperthyroidism for more than 60 years, with no evidence
of increased risk of thyroid cancer or other malignancies.
Its use, however, requires the patient to follow regulations
designed to limit exposure of the general public to
radiation. Public perception of the dangers of radiation,
together with the necessity to follow these regulations,
often prejudices patients against this eective treatment
option. ere is a delay before an eect is seen
(2–3 months); patients often require additional antithyroid drugs, such as thioureylenes (see below), during
this period.
Radioiodine is generally well tolerated, although it may
exacerbate exophthalmos in Graves’ disease. It is
commonly used for patients with toxic multinodular
goitre, for those unable to tolerate sulphur-containing
thioureylenes, or where these drugs have not been
eective.
ioureylenes e thioureylenes (also called
thionamides), which include carbimazole and
propylthiouracil, are the mainstay of treatment for
hyperthyroidism. All members of this drug class have a
thiocarbamide group (S–C–N) (Figure 15.4). Carbimazole,
a pro-drug of methimazole, is the most commonly used
thioureylene.
ioureylenes are competitive inhibitors of the
biosynthesis of T3 and T4, blocking the thyroperoxidase
enzyme and preventing the oxidation of iodide and its
incorporation into thyroglobulin (Box 15.1). is results
in a reduction in T3 and T4 production in the thyroid
gland. Propylthiouracil also prevents the deiodination of
T4 to the more active T3 in the periphery; this may explain
its faster onset of action compared with the other
thioureylenes. e clinical response is slow to develop
because of pre-existing stores of thyroid hormones within
the follicles, and the long half-life of circulating T4
(approximately 7 days).
e thioureylenes have an immunosuppressant eect
which underlies their most dangerous, albeit rare,
adverse eect: bone marrow suppression
(agranulocytosis and neutropenia). Given its potential
seriousness, patients should be warned to report any
sudden severe sore throat associated with fever, common
signs of bone marrow suppression. e eects on the
bone marrow are reversed on stopping treatment.
Gastrointestinal upset and allergic reactions may also be
experienced with these drugs.
Iodide ions e release of thyroid hormones can be
transiently decreased by administration of iodide. (is is
seen as a side eect of iodide-containing medication, e.g.
older cough mixtures containing potassium iodide.) High
doses of iodine can be administered as a solution of
iodine and potassium iodide (Lugol’s solution),
commonly used prior to ablation surgery or in
hyperthyroid crises (thyroid storm; see above). e iodide
blocks thyroid hormone production by inhibiting the
thyroperoxidase enzyme and reducing iodide
organication (see Box 15.1). is causes thyroglobulin to
accumulate, and the number of blood vessels in the
thyroid gland to decrease; the gland becomes smaller and
rmer, facilitating ablation surgery. e inhibitory eect
of iodide, known as the Wol–Chaiko eect, is maximal
after around 10–15 days of continuous administration;
thereafter it diminishes due to an adaptive decrease in
expression of the iodide pump.
Adverse eects of Lugol’s solution include angioedema,
an allergic reaction that results in rapid swelling of the
skin and mucous membranes, which can be lifethreatening. Bronchitis, conjunctivitis, laryngitis, and
S
NN O
Figure 15.4 Thioureylenes used in the treatment of hyperthyroidism.
O
Carbimazole Methimazole Propylthiouracil
S
NNH
HN
NH
O
386 Chapter 15 Thyroid disorders and pharmacological methods of contraception
other cold-type symptoms can occur; such eects are
seen where iodide has been supplied at excessive
concentrations in attempts to reverse endemic goitre (the
result of a decit in dietary iodide).
-adrenoceptor antagonists (-blockers) As detailed
above, many of the symptoms experienced by
hyperthyroid patients result from the increased sensitivity
of -adrenoceptors (tachycardia, tremor, and
nervousness). -Adrenoceptor antagonists, such as
propranolol, are therefore useful in reducing the
symptoms of hyperthyroidism without directly aecting
levels of thyroid hormones. e mechanism of action of
these drugs is covered in Chapter 5, Section 5.2.5.
-Blockers are often used to provide rapid relief from
symptoms in the period before thioureylenes take eect.
15.2.2 Hypothyroidism
Hypothyroidism, where levels of circulating thyroid
hormones are reduced, is more common than
hyperthyroidism in developed countries, aecting 2–5%
of the population. Worldwide, however, the incidence is
far higher, due to hypothyroidism resulting from iodide
deciency (see above).
In Western countries, hypothyroidism is more likely to be
the result of the following.
1. Disease of the thyroid gland (primary
hypothyroidism), usually due to autoimmune
destruction. In Hashimoto’s thyroiditis, T-cells in the
immune system destroy thyroid tissue (cell-mediated
immunity; see Section P3.2.2 in the Introduction to
Part 3 of this book). is leads to decreased levels of
circulating T3 and thyroxine. (ere may rst be a
transient hyperthyroid state, when pre-formed thyroid
hormones are released during the destruction of the
gland.) TSH levels will be high as the pituitary attempts
to stimulate the failing gland; a goitre may develop.
Primary hypothyroidism accounts for >95% of cases in
Western or developed countries, and can be treated
with thyroxine supplementation (see below).
2. Much more rarely, hypothyroidism can result from
reduced release of TSH from the anterior pituitary
(secondary hypothyroidism) or of TRH from the
hypothalamus (tertiary hypothyroidism). In these
cases TRH and/or TSH levels will be reduced, as will
the levels of T3 and thyroxine; a goitre will not develop.
Causes include tumours of the pituitary, and
irradiation of the brain.
Hypothyroidism can (and usually does) follow thyroid
ablation by either surgery or radioiodine treatment. It can
also be induced by some drugs, including iodinecontaining amiodarone and lithium. In addition, some
naturally occurring substances can cause goitre by
inhibiting the iodination of thyroglobulin and therefore
reducing thyroid hormone synthesis. Such goitrogens are
present in plants, e.g. the Brassica genus (cabbages etc.),
and consumption of large quantities may present
problems in some patients with an already dysfunctional
thyroid gland.
Symptoms of hypothyroidism are usually slow in onset
and often mistakenly attributed to ageing. ey include
weight gain, sensitivity to cold, lethargy, bradycardia,
diminished mental responsiveness, poor memory, and
changes to skin tone and hair. Severe hypothyroidism can
lead to coma (myxoedema coma). As mentioned in
Section 15.1.3, cretinism will result if hypothyroidism is
untreated in a newborn.
Treatment of hypothyroidism
Primary hypothyroidism is usually treated with thyroid
hormone replacement therapy using synthetic T4 or T3.
Where iodide deciency is the cause, treatment is with
iodide.
yroxine (T4) e most widely used treatment for
hypothyroidism is levothyroxine (synthetic T4). As it is
identical to the natural hormone, it has a long plasma
half-life by virtue of binding to plasma proteins (see
Section 15.1.1); missing a dose only leads to minimal
uctuations in plasma levels. As a result of the long
half-life, a steady state is reached slowly (approximately
30 days), as is the full therapeutic eect. yroid function
is monitored after 3 months of therapy and used to guide
dosage adjustments; TSH levels should return to normal
levels from their previously elevated state. Monitoring on
an annual basis should continue throughout use.
e adverse eects most commonly experienced are
due to excessive dose, and are therefore similar to
hyperthyroidism: cardiac (atrial brillation, palpitations,
angina pain), neurological (excitability, tremor,
insomnia), and gastrointestinal (diarrhoea,
weight loss).
ere is an important role for counselling of hypothyroid
patients. Lifelong treatment with levothyroxine is
required, and this can present problems with adherence;
patients must be encouraged to continue to take
medication, and not stop because they feel well.
15.3 Contraception 387
Liothyronine (T3) Liothyronine, T3 replacement therapy,
has a more rapid onset of action than levothyroxine, but a
shorter duration of action which necessitates an
15.3 Contraception
Useful terms for this topic
Corpus luteum: Solid mass of steroidogenic cells,
predominantly secreting progesterone.
Follicular phase of the ovarian cycle: First half of
the ovarian cycle when follicles in the ovary mature,
ending with ovulation. Oestradiol is the dominant
hormone in this phase.
Graafian follicle: Fluid-lled structure in the ovary
containing the ovum. It acts as an endocrine unit by
secreting oestrogens.
Luteal phase of the ovarian cycle: Second half of
the ovarian cycle, starting from ovulation. Progesterone
is the dominant hormone in this phase.
Menstrual cycle: The cyclical changes in the ovaries
and lining of the uterus.
Ovarian cycle: The interval between successive
ovulations, divided into the pre-ovulatory follicular
phase and the post-ovulatory luteal phase.
Thyrotoxicosis: Clinically observed effects following
exposure of tissues to excessive concentrations of
thyroid hormones.
e female reproductive system can be manipulated to
prevent conception using drugs that mimic the eects of
the endogenous female sex hormones. In order to
understand how these drugs act, we must rst consider
the female sex steroids and their roles within the ovarian
and menstrual cycles.
15.3.1 Female reproductive hormones
increased dosing frequency. It is usually reserved for the
emergency treatment of hypothyroid coma (myxoedema
coma). Possible side eects match those of levothyroxine.
important progestogen, progesterone, dominates the
second half.
Like other steroid hormones, oestrogens and
progesterone act at intracellular nuclear receptors. ose
for oestrogen (ER and ER) and progesterone (PR-A and
PR-B) are type I nuclear receptors, located in the cytosol
of the target cell. Once the steroid hormone binds, the
ligand–receptor complex is translocated to the nucleus
where it either induces or suppresses gene transcription.
(e mode of action is the same as that of glucocorticoids,
described in Chapter 9, Box 9.2.) In addition, oestrogen
exerts some more immediate non-genomic eects
mediated by cell surface G-protein-coupled receptors.
e eects of oestrogen and progesterone are
summarized in Table 15.2, and their roles in the ovarian
and menstrual cycles are described in detail in the
following sections.
15.3.2 The ovarian and menstrual cycles
e ovarian cycle lasts between 28 and 30 days and
describes the cyclical development and release of a
mature egg (oocyte) from the ovary, accompanied by
changing levels of hormones (Figure 15.6). Each cycle
consists of two phases, the follicular and luteal phases,
and is regulated by complex hormonal relationships
involving the hypothalamus, the anterior pituitary, and
the gonads themselves. e cyclical production of a
mature oocyte is synchronized with changes to the uterus
and vagina (the menstrual cycle), which optimize
conditions for its fertilization and implantation.
e female sex hormones are steroids derived from
cholesterol, as illustrated in Figure 15.5. ere are two
classes: oestrogens and progestogens. e endogenous
oestrogens are oestradiol, oestrone, and oestriol.
Oestradiol is the principal ovarian oestrogen, being
10 times as potent as oestriol and oestrone; oestriol is
mainly secreted during pregnancy by the placenta. e
action of oestrogen dominates the rst half of the female
reproductive cycle (the ovarian cycle), whereas the most
Follicular phase of the ovarian cycle
During this phase, follicles in the ovary which contain the
egg cell, or oocyte, start to develop under the inuence of
two gonadotrophins secreted by the pituitary gland:
follicle-stimulating hormone and luteinizing hormone.
Each follicle contains a primary diploid oocyte (which has
23 pairs of chromosomes, twice the complement of a sex
cell). is oocyte is in a state of meiotic arrest. is primary
oocyte must undergo meiosis to generate a secondary
388 Chapter 15 Thyroid disorders and pharmacological methods of contraception
H
H
HO
Cholesterol side-chain cleavage enzyme
H
Cholesterol
O
H
H
O
H
Progesterone
17-α-hydroxylase
O
H
H
O
OH
H
17α-hydroxy-progesterone
OH
3-β-HSD
3-β-HSD
17,20 Lyase
17-β-HSD
H
H
HO
H
Pregnenolone
17-α-hydroxylase
H
H
HO
H
17α-hydroxy-pregnenolone
17, 20 Lyase and 3-β-HSD
O
H
H
O
H
Androstenedione
O
O
OH
H
Aromatase
O
H
O
Testosterone
H
H
Aromatase
H
H
Oestrone
HO
OH
17-β-HSD
H
H
H
HO
Oestradiol
Figure 15.5 Synthesis of female sex hormones.
HSD, hydroxysteroid dehydrogenase; hormones highlighted in blue are the main female sex
hormones.
15.3 Contraception 389
Table 15.2 The effects of oestrogens and progesterone
Effect of oestrogens Effect of progesterone
During puberty
Growth of the uterus and development of secondary
sexual characteristics (e.g. breasts)
Deposition of fat
Epiphysis closure, terminating growth of long bones
During the menstrual cycle
Endometrial proliferation
Secretion of increased volumes of mucus by the cervix,
which nourishes and is penetrable by sperm
During pregnancy
Preparation of breast tissue for lactation
Development of the uterine smooth muscle, and
increased uterine blood supply
Fluid retention
Cellular/other effects
Retention of sodium and water (mineralocorticoid action;
see Chapter 9)
Potentially beneficial increase in levels of high density
lipoprotein (‘good’ cholesterol; see Chapter 6)
Increased coagulability of blood (increased risk of venous
thrombus formation; see Chapter 4)
Increased apoptosis of osteoclasts (bone-absorbing cells)
Endometrial development—increase in number of blood
vessels and secretory glands
Rise in body temperature
Secretion of smaller volume of impenetrable mucus by cervix
Preparation of breast tissue for lactation
Decreased contractility of uterine smooth muscle
Formation of a cervical mucus plug to prevent uterine
infection
haploid oocyte (which has 23 unpaired chromosomes, as
is normal for a sex cell), which can subsequently be
fertilized (see below). e primary oocytes are surrounded
by follicular cells which secrete oestrogens, notably
oestradiol. As the follicles develop and grow, the levels of
hormone rise (see Figure 15.6); follicles can therefore be
regarded as endocrine units. Of the follicles recruited at
the start of the follicular phase (typically around 15–20),
usually only one develops into a mature Graaan follicle,
up to 25 mm in diameter (see Figure 15.7) is follicle may
correspond to that with the highest number of surface
receptors for follicle-stimulating hormone, making it
extremely sensitive to hormonal stimulation. A surge in
luteinizing hormone (see below) triggers the rupture of
the Graaan follicle on the surface of the ovary, releasing
the ovum (ovulation). Typically, this occurs at around the
mid-point (day 14) of the ovarian cycle. e rupturing of
the follicle is achieved by enzymes, such as collagenase
and gelatinase, released from the follicular cells under the
inuence of luteinizing hormone. ese enzymes digest
the connective tissue surrounding the oocyte, particularly
in the stigma region (see Figure 15.7). Just before
ovulation, the ovum goes through meiosis to generate the
haploid oocyte. (e second cell generated receives very
little of the cytoplasm during meiosis, and becomes the
rst polar body which subsequently dies.) Ovulation
marks the end of the follicular phase, and the start of the
luteal phase of the ovarian cycle.
Luteal phase of the ovarian cycle
Under the inuence of luteinizing hormone, the cells of
the ruptured Graaan follicle proliferate and grow,
becoming a solid mass of cells, the corpus luteum,
capable of secreting large amounts of progesterone and
smaller amounts of oestrogen. e corpus luteum
continues to increase in size for around 8–9 days after
ovulation, reaching up to 5 cm in diameter, but if
fertilization has not occurred, it then starts to degenerate.
is process will be complete within about 14 days of its
formation, and the luteal phase of the ovarian cycle is
over. Another set of follicles will be recruited, as another
follicular phase begins.
The menstrual cycle
e cyclical events of the ovarian cycle described above
cause changes within the uterus, and give rise to the
menstrual cycle. Under the inuence of rising
oestrogen levels in the follicular phase of the ovarian
cycle, the myometrium (outer smooth muscle layer) and
390 Chapter 15 Thyroid disorders and pharmacological methods of contraception
Graafian follicle
Oestrogen
Hypothalamus
GnRH
Anterior
pituitary
LHFSH
Ovary
Ovulation
CL
Progesterone
LH
FSH
Stromal cells
Stigma (stalk
of cells)
Figure 15.7 A Graafian follicle.
The oocyte is enclosed in a fluid-filled cavity (follicular antrum)
which is surrounded by an inner layer of granulosa cells and an
outer layer of thecal cells. These cells cooperate in the synthesis
of oestrogen. Firstly, the thecal cells are stimulated by luteinizing
hormone to produce androgens. These then diffuse to the inner
granulosa cell layer where they are converted to oestrogens
under the control of follicle-stimulating hormone. At ovulation the
stigma is disrupted by enzymatic action to release the oocyte
from the follicle.
Adapted from Pocock G, Richards CD, Richards DA, Human Physiology
(4th edn), 2013. By permission of Oxford University Press.
Theca externa
Theca interna
Granulosa cells
Antrum lled with
follicular uid
Oocyte
Membrana
propria
0714 21 28
Follicular phase
Figure 15.6 Phases of the ovarian cycle.
GnRH, gonadotrophin-releasing hormone; FSH, folliclestimulating hormone; LH, luteinizing hormone; CL, corpus luteum.
Luteal phase
Days
of cycle
endometrium (inner vascularized lining) of the uterus are
stimulated to proliferate. Oestrogens stimulate the
endometrium to express receptors for progesterone, the
levels of which rise in the luteal phase of the ovarian
cycle. e progesterone then acts to increase the number
of blood vessels and secretory glands in the thickened
endometrial lining. e combined actions of oestrogen
and progesterone on the uterus optimize the conditions
for implantation of the blastocyst following fertilization.
Cells in the cervical epithelium produce mucus, the
composition and volume of which change under the
inuence of the female steroids. During the second half of
the follicular phase under oestrogen dominance, the
cervix produces larger volumes of mucus, rich in mucins
and nutrients. e consistency of this oestrogenic mucus
allows penetration by sperm, and maximum production
coincides with ovulation. e mucus provides a source of
nutrients to sustain the sperm as they pass through the
cervix.
Under progestogen dominance in the luteal phase,
however, a smaller volume of mucus is produced which
has dierent properties. e mucus (G mucus) now has a
lower pH and is much thicker. It is not conducive to the
survival of sperm, nor are they able to penetrate it.
Production of this type of mucus is the major mechanism
underlying the contraceptive action of exogenously
administered progestogens, which produce a hostile
environment to sperm even in the presence of the high
oestrogen levels that occur at ovulation.
If fertilization and implantation do not occur,
menstruation will follow at the end of the luteal phase of
the ovarian cycle, around 14 days after ovulation.
Conventionally, the onset of menstruation is denoted as
the start of the menstrual cycle, coinciding with the early
15.4 Pharmacological methods of contraception 391
part of the follicular phase of the ovarian cycle.
Menstruation typically lasts 4–6 days and is prompted by
the marked drop in progesterone and oestrogen that
results from the degeneration of the corpus luteum. e
steroidogenic cells of the corpus luteum die, and the
structure becomes lled with scar tissue—the corpus
albicans. is is eventually reabsorbed by the ovary.
e endometrial lining is shed from the vagina as a
consequence of removal of its hormonal support. e
reduced hormone levels also stimulate release of a uterine
prostaglandin, which causes vasoconstriction of
endometrial blood vessels. is results in necrosis of the
endometrial lining, and of the blood vessels themselves.
e prostaglandin stimulates contractions of the uterine
smooth muscle, encouraging the expulsion of the blood
and damaged endometrium. Where excessive, these
uterine contractions are experienced as menstrual cramps.
When fertilization occurs the implanted blastocyst
secretes chorionic gonadotrophin, which maintains the
steroid-secreting activity of the corpus luteum until
around the seventh week of pregnancy. (e production of
this gonadotrophin is detected in urine, and forms the
basis of early pregnancy tests. e structure of chorionic
gonadotrophin is very similar to that of thyroidstimulating hormone, and occasionally leads to a transient
hyperthyroidic state in the early stage of pregnancy.)
Beyond this point the fetus and placenta act in concert to
secrete the hormones essential for pregnancy.
15.3.3 Control of the female reproductive
cycle
e female reproductive system is controlled by two
gonadotrophic hormones from the anterior pituitary:
follicle-stimulating hormone and luteinizing hormone.
eir secretion is in turn regulated by gonadotrophinreleasing hormone (GnRH) from the hypothalamus.
Oestrogen and progesterone exert feedback eects at the
level of both the pituitary and the hypothalamus.
In the follicular phase of the ovarian cycle both
luteinizing hormone and follicle-stimulating hormone
are required. e oocyte-containing follicles are
uid-lled cavities enclosed by an inner layer of
granulosa cells, and an outer layer of thecal cells (Figure
15.7). ese two cell types act in concert to produce
oestrogen from its cholesterol precursor, and are
dierentially stimulated by luteinizing hormone and
follicle-stimulating hormone. ecal cells are stimulated
by luteinizing hormone to produce androgens from
cholesterol, but lack the aromatase enzyme required for
conversion to oestrogens (see Figure 15.5). Instead, the
androgens diuse to nearby aromatase-containing
granulosa cells to be converted to oestrogens; this
conversion is promoted by follicle-stimulating hormone.
Some of the oestrogen generated by the follicle is secreted
into the blood, and levels of this hormone rise. is rising
level of oestrogen has a profound eect on the anterior
pituitary, inhibiting secretion of follicle-stimulating
hormone. During the second part of the follicular phase
the levels of follicle-stimulating hormone start to decline,
and those of the luteinizing hormone plateau. e level
of oestrogen being secreted by the Graaan follicle starts
to rise.
e oestrogen exerts a negative feedback inuence on the
production of luteinizing hormone from the anterior
pituitary, keeping levels low. e growing follicle,
however, releases ever-increasing amounts of hormone
and, once a critical concentration is reached and
maintained in the circulation, the feedback eect of
oestrogen at both the hypothalamus and the pituitary
gland switches from negative to positive. e dramatic
surge in luteinizing hormone facilitates release of the
oocyte from the Graaan follicle (see above and
Figure 15.6). ere is also a lesser surge in folliclestimulating hormone. Once the levels of oestrogen fall as
the follicle collapses, the levels of luteinizing hormone
and follicle-stimulating hormone also drop, no longer
sustained by the positive feedback stimulus.
During the luteal phase, luteinizing hormone supports the
synthesis of hormones and in particular progesterone
from the corpus luteum. Progesterone has a negative
feedback eect on the secretion of luteinizing hormone
and follicle-stimulating hormone, keeping their levels low.
15.4 Pharmacological methods of contraception
e most common form of pharmacological
contraception is the oral contraceptive pill. ere are two
main types of pill: combined synthetic oestrogens and
progestogens, and progestogen-only. e mechanisms by
which these synthetic steroid hormones lead to
contraception is by modifying or inhibiting the events of